Cerebellum最新文献

As brain-machine interfaces (BMI) are growingly used in clinical settings, understanding how to apply brain stimulation is increasingly important. Despite the emergence of optogenetic techniques, ethical and medical concerns suggest that interventions that are safe and non-invasive, such as Transcranial Alternating Current Stimulation (tACS), are more likely to be employed in human in the near future. Consequently, the question of how and where to apply current stimulation is becoming increasingly important for the efficient neuromodulation of both neurological and psychiatric disorders. In this edition of The Cerebellum, Mourra et al. demonstrate how ctACS influences cerebellar output at both single-cell and population levels by stimulating Crus I in rats. As the neuron generating this output serves as a crucial convergence and divergence center in the nervous system, it can be leveraged as a strategic hub to target multiple brain structures and influence various behaviors. Accordingly, the discovery that neurons in this relatively deep brain region can be indirectly entrained through Purkinje neuron activation and optimal frequency around 80 Hz could be highly relevant for future medical interventions. In light of these findings, high-γ-tACS might be more effective in humans compared to the more commonly used low-γ (50 Hz) or θ-tACS (5 Hz). This could enhance the chance of cerebellar tACS being utilized in clinical settings and BMI.

Variants in KIF1A are associated with hereditary spastic paraplegia (SPG30), which can manifest in both pure and complex forms. We describe a Japanese family with a novel KIF1A variant presenting with a complex form of SPG30. Patient 1, a 69-year-old woman, experienced progressive gait disturbance due to spastic paraparesis and cerebellar atrophy, and intellectual disability. Patient 2, the daughter of Patient 1, exhibited similar symptoms with more severe dysarthria. Patients 1 and 2 shared a heterozygous c.173 C > G (p.Ser58Trp) variant in the motor domain of KIF1A (NM_001244008.2), which is classified as likely pathogenic. This family highlights the role of autosomal dominant inheritance in a complex form of SPG30, expanding the understanding of its genetic basis and clinical presentation.

Spinocerebellar ataxias (SCAs) are a diverse and heterogeneous group of inherited neurodegenerative disorders marked by progressive ataxia and cerebellar degeneration. This case report details an 11-year-old Indian boy with childhood-onset ataxia and severe sensorineural hearing loss, a rarely reported concomitance in pediatric neurology. Genetic analysis identified a unique heterozygous 3' splice site variant in the PNPT1 gene (c.2014-3 C > G) of pathogenic significance, confirming the diagnosis of SCA25. This case highlights the phenotypic and genotypic heterogeneity of PNPT1 gene-related SCA25 and suggests an autosomal dominant inheritance pattern with low penetrance. It underscores the need for functional studies to further validate the splice variant reported herein and emphasizes the importance of a high index of suspicion for genetic analysis and genetic counselling in children with concurrent hearing loss and progressive ataxia, even in the absence of a clear autosomal dominant inheritance pattern.

Crossed cerebellar diaschisis(CCD) involves reduced metabolism and blood flow in the cerebellar hemisphere contralateral to a supratentorial lesion. ASL is a valuable tool for quantifying regional cerebral blood flow. This study assesses ASL-MRI's ability to detect CCD in epilepsy using integrated ¹⁸F-FDG PET/MRI and compares ASL with PET images in evaluating CCD. 74 patients with drug-refractory epilepsy who underwent integrated ¹⁸F-FDG PET/MRI pre-surgery and CT/MRI post-surgery was analysed. Regions of interest were outlined on MRI images and simultaneously transferred to PET and ASL images. CCD detection was evaluated visually and semi-quantitatively using the absolute asymmetry index (AIabs). Out of 74 patients, PET detected CCD in 24 (32.43%) and ASL in 18 (24.32%), with no significant difference between them (P = 0.274). Based on the PET results, the ROC curve for ASL's diagnostic accuracy for CCD showed an area under the curve of 0.69 (P = 0.008), an accuracy of 75.68%, a sensitivity of 50%, a specificity of 88%, a positive predictive value (PPV) of 66.67%, and a negative predictive value (NPV) of 78.57%. Four CCD types were identified: both PET and ASL positive (16.22%), PET positive and ASL negative (16.22%), ASL positive and PET negative (8.10%), and both negative (59.46%). AIabs correlation was positive between PET and ASL in the epileptic zone (r = 0.658, P < 0.001) and cerebellum (r = 0.407, P < 0.001). In ASL CCD-positive cases, AIabs showed a negative correlation between the epileptic zone and cerebellum (r=-0.581, P = 0.011), while in both PET and ASL CCD-positive cases, AIabs correlation was positive (r = 0.670, P = 0.017). ASL can be used as a method for evaluating CCD, and when combined with FDG-PET, it can further enhance its diagnostic accuracy for CCD. In CCD-positive cases, a notable discrepancy was observed: no correlation in PET images but a correlation in ASL images between the supratentorial epileptic zone and contralateral cerebellar hemisphere, indicating CCD might be linked to regional cerebral blood flow changes.

In term neonates with hypoxic-ischemic encephalopathy (HIE), cerebellar injury is becoming more and more acknowledged. Animal studies demonstrated that Purkinje cells (PCs) are especially vulnerable for hypoxic-ischemic injury. In neonates, however, the extent and pattern of PC injury has not been investigated. The aim of this study was to characterize the morphology and distribution of PCs in the cerebellar vermis of term born neonates with HIE. Twenty-two term born neonates with severe HIE, several of which received therapeutic hypothermia, who underwent post-mortem autopsy of the brain including cerebellar vermis within three to five days after birth were included. Haematoxylin & Eosin (H&E) stained sections of the vermis were used to determine total PC count and morphology (normal, abnormal or non-classified) at the bases and crowns of the folia and of the lobules in both the anterior and posterior lobes. Differences in PC count and PC morphology between the anterior and posterior lobe and between the bases and crowns were compared. The total number of PCs was significantly higher at the crowns compared to the bases (p < 0.001) irrespective of the precise location. Besides, PCs at the bases more often had an abnormal morphology. Also, a significant difference between the injury in the anterior and posterior lobe was observed, notably at specific microscopic locations with more abnormal PCs in the posterior lobe. The number of PCs scored as abnormal was increased in the bases compared to the crowns, which might resemble supratentorial ulegyria.

The vestibular processing regions of the cerebellum integrate vestibular information with other sensory modalities and motor signals to regulate balance, gaze stability, and spatial orientation. A class of excitatory glutamatergic interneurons known as unipolar brush cells (UBCs) are highly concentrated within the granule cell layer of these regions. UBCs receive vestibular signals directly from primary vestibular afferents and indirectly from mossy fibers. Each UBC excites numerous granule cells and could contribute to computations necessary for balance-related motor function. Prior research has implicated UBCs in motor function, but their influence on balance performance remains unclear, especially in aged mice that have age-related impairment. Here we tested whether UBCs contribute to motor coordination and balance by disrupting their activity with chemogenetics in aged and young mice. Age-related balance deficits were apparent in mice > 6 months old. Disrupting the activity of a subpopulation of UBCs caused aged mice to fall off a balance beam more frequently and altered swimming behaviors that are sensitive to vestibular dysfunction. These effects were not seen in young (7-week-old) mice. Thus, disrupting the activity of UBCs impairs mice with age-related balance issues and suggest that UBCs are essential for balance and vestibular function in aged mice.

Patients with Hereditary Spastic Paraplegia (HSP) report reduced quality of life (QoL) compared to the general population. Generic QoL measures do not address disease-specific aspects such as spasticity, access to specialty HSP clinics, and bladder symptoms. We designed and validated a HSP-specific QoL scale (HSPQoL), intended for use in standard clinical settings and clinical trials. HSP-specific items were added to the RAND 36-Item Short Form Health Survey (SF-36) to form HSPQoL. Following literature review/expert input, 23 items were presented to a panel of HSP clinicians, patients, and patient representatives (n = 12) using a modified Delphi process. Items were ranked for clarity and relevance (inclusion criteria: 80% consensus). 21/23 items met the inclusion criteria. Interviews with patients (n = 5) assessed suitability, comprehension, clarity, and response options to additional items. Based on cognitive interview results, items were modified (n=4), removed (n=7), or added (n=3). Sixty-one patients completed the HSPQoL and EQ5D-5L for evaluation of construct validity and 19 patients repeated the HSPQoL for evaluation of test-retest reliability. 15/17 additional items moderately to strongly correlated with pre-existing SF-36 subscores (Spearman correlation 0.319-0.771, p < 0.05). Exploratory factor analyses showed high percentage of variance in the first component (> 45%). HSPQoL demonstrated good internal consistency (Cronbach alpha 0.94), test-retest reliability (ICC 0.957), and convergent validity with EQ5D-5L (r = 0.725). In conclusion, demonstrated validity and reliability of the HSPQoL confirms consideration of its use for assessing specific QoL in individuals with HSP.

Friedreich's Ataxia (FRDA) is the most common autosomal recessive ataxia worldwide and is caused by biallelic unstable intronic GAA expansions at FXN. With its limited therapy and the recent approval of the first disease-modifying agent for FRDA, the search for biological markers is urgently needed to assist and ease the development of therapies. MiRNAs have emerged as promising biomarkers in various medical fields such as oncology, cardiology, epilepsy and neurology as well. Cell-free plasmatic miRNAs have potential advantages as biomarkers because of their size, stability against blood RNases, relative ease of obtaining, storage and measurement. In this study, we attempted to characterize the plasma miRNA signature (RNA-Seq followed by qRT-PCR) and its clinical/structural correlates in a cohort of Brazilian patients with FRDA. Our results showed that miR-26a-5p is upregulated and miR-15a-5p is downregulated. The first was correlated with age at onset, cerebellum volume, spinal cord cross-sectional area (C2-CSA) and the left ventricle mass (LV_Mass). For the miR-15a-5p, significant correlations were found with cerebellum volume, spinal cord eccentricity and LV_Mass. It has been previously hypothesized that these miRs target BDNF, modulating its expression and, when this gene is downregulated, it leads to neuronal loss, explaining the ataxic phenotype and our results reinforce this hypothesis. The miR-26a-5p was already associated with cardiomyocyte hypertrophy through the increased NLRP3 inflammasome activity, which is indirectly linked with cardiac hypertrophy. Considering that, we propose these miRNAs as possible prognostic biomarkers for FRDA. However, longitudinal studies are still needed to validate their clinical use.

Clinically-relevant variants in the STUB1 gene have been associated with an autosomal dominant spinocerebellar ataxia 48 (SCA48), a recently described inherited neurodegenerative condition that is characterised by cognitive and psychiatric changes. To describe the clinical phenotype and genetic findings of three new Australian probands with STUB1 to expand the current understanding of the spectrum of clinical presentation and natural history of SCA48. Clinical and genetic review of patients diagnosed with SCA48 ataxia drawn from our centres. The third case was derived from a collaborating centre (Royal Brisbane Hospital). We identified three unrelated SCA48 patients with heterozygous pathogenic STUB1 variants. All presented with slowly progressive cerebellar ataxia with tremor and additional findings of dysarthria, parkinsonism, hypertonia, cognitive and psychiatric symptoms. Age of onset varied from 34 to 65 years of age. Brain MRI showed significant diffuse cerebellar atrophy, affecting the vermis and cerebellar hemispheres. We identified two novel pathogenic variants of STUB1 gene, and one previously reported pathogenic variant. Genetic testing for intermediate expansions of TBP (SCA17) identified TBP repeats within the normal range of 25-40 in all 3 probands. Our case series expands the clinical spectrum of SCA48. We highlight the importance of tremor as part of the clinical phenotype including upper limb rest tremor and Parkinsonian signs. Our cases lacked pathological TBP expansions and provide additional evidence that STUB1 (SCA48) can manifest as a monogenic disease.

Whereas several studies have reported on quantitative oculomotor and vestibular measurements in spinocerebellar ataxia type 6 (SCA6), selecting the most suitable paradigms remains challenging. We aimed to address this knowledge gap through a systematic literature review and providing disease-specific recommendations for a tailored set of eye-movement recordings in SCA6. A literature search (MEDLINE, Embase) was performed focusing on studies reporting on quantitative oculomotor and/or vestibular measurements in SCA6-patients. Oculomotor and vestibular parameters were extracted and correlations with various epidemiologic and clinical parameters were sought. Twenty-two studies were included reporting on 154 patients. Abnormalities observed included reduced pursuit gain (58/69), frequent square-wave jerks (23/40), spontaneous downbeat nystagmus (DBN, 34/55) and triggered nystagmus including positional nystagmus (25/34) and vertical ("perverted") head-shaking nystagmus (21/34), gaze-evoked nystagmus (48/70) and angular vestibulo-ocular reflex (aVOR)-suppression (21/25), and high-frequency aVOR-deficits (26/33). For horizontal visually-guided saccades (VGS), changes in metrics (36/66) were frequently observed, whereas saccade velocity was usually preserved (39/44) and saccade latency within normal limits. Reduced high-frequency aVOR gains, VGS-latency and metrics correlated with disease severity. Longitudinal data indicated deterioration of individual video-head-impulse testing gains over time. A broad range of oculomotor and vestibular domains are affected in SCA6. Impairments in pursuit, saccade metrics, gaze-holding (gaze-evoked nystagmus, DBN) and high-frequency aVOR were most frequently identified and as such, should be prioritized as disease markers. Quantitative oculomotor testing in SCA6 may facilitate an early diagnosis and prove valuable in monitoring disease progression.